Pyrrolo[2,1-c][1,4]benzodiazepines antitumour antibiotics are commonly known as anthramycin class of compounds. In the last few years, a growing interest has been shown in the development of new pyrrolo[2,1-c][1,4]benzodiazepines (PBDs). These antibiotics react covalently with DNA to form an N2-guanine adduct that lies within the minor groove of duplex DNA via an acid-labile aminal bond to the electrophilic imine at the N10-C11 position. (Kunimoto, S. Masuda, T. Kanbayashi, N. Hamada, M. Naganawa, H. Miyamoto, M. Takeuchi, T. and Unezawa, H. J. Antibiot., 1980, 33, 665.; Kohn, K. W. and Speous, C. L. J. Mol. Biol., 1970, 51, 551.; Hurley, L. H. Gairpla, C. and Zmijewski, M. Biochem. Biophys. Acta., 1977, 475, 521.; Kaplan, D. J. and Hurley, L. H. Biochmestry, 1981, 20, 7572). The molecules have a right-handed twist, which allows them to follow the curvature of the minor groove of B-form double-stranded DNA spanning three base pairs. Recently PBD dimers have been developed that comprises two C2-exo-methylene-substituted DC-81 subunits tethered through their C-8 position via an inert propanedioxy linker. (S. J. Gregson, P. W. Howard, J. A. Hartely, N. A. Brooks, L. J Adams, T. C. Jenkins, L. R. Kelland, and D. E. Thurston. J. Med. Chem., 2001, 44, 737). A recent development has been the linking of two PBD units through their C-8 positions to give bisfunctional alkylating agents capable of cross-linking DNA (Thurston, D. E. Bose, D. S. Thomson, A. S. Howard, P. W. Leoni, A. Croker, S. J. Jenkins, T. C. Neidle, S. and Hurley, L. H. J. Org. Chem., 1996, 61, 8141–8147). Recently, a noncross-linking mixed imine-amide PBD dimers have been synthesized that have significant DNA binding ability and potent anti tumour activitiy (Kamal, A.; Laxman, N.; Ramesh, G.; Ramulu, P and Srinivas, O. U.S. Pat. No. 636,233. dt 26-03-2002.; Kamal, A.; Ramesh, G.; Laxman, N.; Ramulu, P.; Srinivas, O.; Neelima, K.; Kondapi, A. K.; Srinu, V. B.; Nagarajaram, H. M. J. Med Chem. 2002, 45, 4679).
Naturally occurring pyrrolo[2,1-c][1,4]benzodiazepines belong to a group of antitumour antibiotics derived from Streptomyces species. Recently, there is much impetus for the PBD systems as they can recognize and bind to specific sequence of DNA. Examples of naturally occurring PBD's include anthramycin, DC-81, tomaymycin, sibiromycin and neothramycin.
However, the clinical efficacy for these antibiotics is hindered by several limitations, such as poor water solubility and cardiotoxicity and development of drug resistance and metabolic inactivation.